PMID- 38417838 OWN - NLM STAT- MEDLINE DCOM- 20240314 LR - 20240316 IS - 1744-8069 (Electronic) IS - 1744-8069 (Linking) VI - 20 DP - 2024 Jan-Dec TI - Esketamine inhibits the c-Jun N-terminal kinase pathway in the spinal dorsal horn to relieve bone cancer pain in rats. PG - 17448069241239231 LID - 10.1177/17448069241239231 [doi] LID - 17448069241239231 AB - Cancer-induced bone pain (CIBP) is one of the most common and feared symptoms in patients with advanced tumors. The X-C motif chemokine ligand 12 (CXCL12) and the CXCR4 receptor have been associated with glial cell activation in bone cancer pain. Moreover, mitogen-activated protein kinases (MAPKs), as downstream CXCL12/CXCR4 signals, and c-Jun, as activator protein AP-1 components, contribute to the development of various types of pain. However, the specific CIBP mechanisms remain unknown. Esketamine is a non-selective N-methyl-d-aspartic acid receptor (NMDA) inhibitor commonly used as an analgesic in the clinic, but its analgesic mechanism in bone cancer pain remains unclear. We used a tumor cell implantation (TCI) model and explored that CXCL12/CXCR4, p-MAPKs, and p-c-Jun were stably up-regulated in the spinal cord. Immunofluorescence images showed activated microglia in the spinal cord on day 14 after TCI and co-expression of CXCL12/CXCR4, p-MAPKs (p-JNK, p-ERK, p-p38 MAPK), and p-c-Jun in microglia. Intrathecal injection of the CXCR4 inhibitor AMD3100 reduced JNK and c-Jun phosphorylations, and intrathecal injection of the JNK inhibitor SP600125 and esketamine also alleviated TCI-induced pain and reduced the expression of p-JNK and p-c-Jun in microglia. Overall, our data suggest that the CXCL12/CXCR4-JNK-c-Jun signaling pathway of microglia in the spinal cord mediates neuronal sensitization and pain hypersensitivity in cancer-induced bone pain and that esketamine exerts its analgesic effect by inhibiting the JNK-c-Jun pathway. FAU - Duan, Chenxia AU - Duan C AD - Department of Anesthesiology, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China. RINGGOLD: 117958 FAU - Zhu, Yi AU - Zhu Y AD - Department of Anesthesiology, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China. RINGGOLD: 117958 FAU - Zhang, Zhuoliang AU - Zhang Z AD - Department of Anesthesiology, Suzhou Municipal Hospital, Xuzhou Medical University, Suzhou, China. RINGGOLD: 117958 FAU - Wu, Tiantian AU - Wu T AD - Department of Histology and Embryology, State Key Laboratory of Reproductive Medicine, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China. RINGGOLD: 271667 FAU - Shen, Mengwei AU - Shen M AD - Department of Anesthesiology, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China. RINGGOLD: 117958 FAU - Xu, Jinfu AU - Xu J AD - Department of Histology and Embryology, State Key Laboratory of Reproductive Medicine, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China. RINGGOLD: 271667 FAU - Gao, Wenxin AU - Gao W AD - Department of Histology and Embryology, State Key Laboratory of Reproductive Medicine, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China. RINGGOLD: 271667 FAU - Pan, Jianhua AU - Pan J AD - Department of Anesthesiology, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China. RINGGOLD: 117958 FAU - Wei, Lei AU - Wei L AUID- ORCID: 0009-0008-2951-8467 AD - Department of Anesthesiology, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China. RINGGOLD: 117958 FAU - Su, Huibin AU - Su H AD - Department of Anesthesiology, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China. RINGGOLD: 117958 FAU - Shi, Chenghuan AU - Shi C AD - Department of Anesthesiology, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China. RINGGOLD: 117958 LA - eng PT - Journal Article PL - United States TA - Mol Pain JT - Molecular pain JID - 101242662 RN - 50LFG02TXD (Esketamine) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - 0 (Analgesics) RN - 690G0D6V8H (Ketamine) SB - IM MH - Humans MH - Rats MH - Animals MH - *Cancer Pain/metabolism MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Rats, Sprague-Dawley MH - Pain/metabolism MH - *Bone Neoplasms/complications MH - Spinal Cord/metabolism MH - Mitogen-Activated Protein Kinases/metabolism MH - Spinal Cord Dorsal Horn/metabolism MH - Analgesics/pharmacology MH - Hyperalgesia/metabolism MH - *Ketamine PMC - PMC10938627 OTO - NOTNLM OT - X-C motif chemokine ligand 12 OT - X-C motif chemokine receptor 4 OT - c-Jun OT - c-Jun N-terminal kinase OT - cancer-induced bone pain OT - esketamine COIS- Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Schematic overview plotted by Figdraw. The authors declare that the study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2024/02/29 00:42 MHDA- 2024/03/14 06:46 PMCR- 2024/03/13 CRDT- 2024/02/28 20:12 PHST- 2024/03/14 06:46 [medline] PHST- 2024/02/29 00:42 [pubmed] PHST- 2024/02/28 20:12 [entrez] PHST- 2024/03/13 00:00 [pmc-release] AID - 10.1177_17448069241239231 [pii] AID - 10.1177/17448069241239231 [doi] PST - ppublish SO - Mol Pain. 2024 Jan-Dec;20:17448069241239231. doi: 10.1177/17448069241239231.